Pursuant to our discovery (1971) of a photochemical route to fluoroimidazoles, we have found that various fluoro analogs of bioimidazoles (histamine, histidine, etc.) show a variety of useful properties as substrates and inhibitors. For example, 2-fluoro-L-histidine not only is incorporated into microbial and animal protein in place of histidine, but also serves as an antibacterial, antiviral and antileukemic agent. Recent studies with labelled amino acids reveal that this analog also limits the uptake of several other amino acids into the cell. Such results provided an impetus to develop synthetic methods for other new analogs of histamine and histidine with substituents at C-2, C-4 or both. Analogs containing all the major functional groups are now on hand. Synthesis of 2-halohistidines proved especially difficult: a general procedure has now been developed in which 2-diazohistidine is decomposed in the presence of halide ion and copper powder. Quite surprisingly, 2-iodohistidine is active against microorganisms which are unaffected by 2-fluorohistidine. The azido analogs are of interest for photoaffinity labelling of receptors and enzymes. The trifluoromethyl analogs are labile in mildly alkaline media, making them potentially useful as receptor affinity labels for use in vivo. Toward this end, the isomeric trifluoromethylhistidine analogs of TRH have been synthesized and are undergoing biological evaluations. Although 2-CF3-His-TRH fails to bind to pituitary cells in vitro and fails to release prolactin in this system, the compound does release prolactin in vivo; this result suggests that the brain contains nonpituitary receptors for TRH which also stimulate prolactin release. The use of TRH for diagnosis of hypothalamic dysfunction is limited by its powerful cardiovascular effects--large increases in heart rate and blood pressure. The 2-CF3 analog is 5-6 times as effective as TRH in promoting prolactin release but has no significant cardiovascular effects--thus making it a potentially valuable diagnostic reagent.